A cancer is caused by uncontrolled growth of cells (neoplasia) and there are over 100 cancer types. Abnormal growth of cells creates a mass of cells (tumor), and this mass of cells penetrates surrounding tissues and spreads to other parts of the body (metastasis).
An important matter to consider when administering an effective drug for the treatment of a disease or the diagnosis of the disease region to a human body is how much of the administered effective ingredient reaches the disease region, that is, the problem of drug delivery efficiency. The effective ingredient may reach an unwanted normal tissue and act to cause side effects, and the amount of drug that reaches the disease region may decrease, resulting in the failure of treatment.
The drugs that have treatment effects for some diseases show strong toxicity to normal tissues or cells and, therefore, they pose problems of which their side effects or cell toxicity are greater than the treatment effect for the disease. Anti-cancer drugs act on normal tissue cells and have adverse effect on normal tissue cells, rather than removing cancer tissues or having treatment effect.
Over 1,300 anti-cancer drugs are known to the public. However, such anti-cancer drugs are often toxic to normal tissue and, thus, have side effects. In addition, since the delivery of anti-cancer drugs to cancer tissues are low due to the characteristics of cancer tissues, the treatment effects are low compared to the side effects.
Particularly, due to heterogeneity, that traces and administers drugs by using the affinity the phenomenon that cancer tissue cells produce various type of replicated tumor cells, it is difficult to utilize a method that traces cancer cells and administers drugs by using the affinity between the receptor of cancer cells and the nanoformulated ligands, which is frequently used for nanoformulated drugs. Thus, it is difficult to treat cancers by using the nanoformulated drugs.
Furthermore, such heterogeneous extracellular matrix of cancer tissues impedes drug penetration which reduces drug exposure and gradually induces drug-resistance. The cancer tissues having these characteristics are difficult to be treated by targeted therapy using antibody markers due to the heterogeneity of cancer cells.
However, due to abnormally rapid division rate of cancer cells and fast growth rate of cancer tissues, cancer tissues are loose and have intercellular cavities therein, compared to normal tissues. In addition, the surface of a cancer tissue includes a number of holes of approximately 100 nm size, has the acidity of less than pH 6.0, and is negatively charged.
Tumors in patients generally contain heterogeneous cell populations, and tumor heterogeneity greatly influences the effectiveness of the receptor-ligand targeting strategies that are most popularly used in cancer nanotechnology. In addition, the heterogeneous tumoral extracellular matrix impedes drug penetration which reduces drug exposure and gradually induces drug-resistance. The tumor microenvironment exhibits an increased interstitial fluid pressure caused by leaky vasculature, poor lymphatic drainage, and a high density of cells and their related matrices.
Therefore, the penetration of nanoparticle-based drugs is limited to the tumor peripheral region with little diffusion of therapeutic nanoparticles into the tumor interstitial space. The physiological and physical mechanism of drug resistance as a whole is a major cause of the failure of most cancer treatments. Although nanoparticles of small size and multi-functionality are emerging as the next-generation anti-cancer agents, there remain great challenges to the development of ‘smart’ nanoparticles that can specifically respond to tumor-related stimuli in order to overcome the aforementioned tumoral barriers.
Self-assembly provides a simple, reproducible and inexpensive way of producing ensembles of nanoparticles with unique plasmonic, photoluminescent, and magnetic properties in a controllable manner. Several stimulus-responsive assembled nanostructures have been thoroughly examined as bio- or chemo-sensors in vitro (Rosi, N. L.; Mirkin, C. A. Chem. Rev. 2005, 105, 1547; Cao, Y C.; Jin, R.; Mirkin, C. A. Science 2002, 297, 1536; Zagorovsky, K.; Chan, W. C. W. Angew. Chem., Int. Ed. 2013, 52, 3168; Taton, T. A.; Mirkin, C. A.; Letsinger, R. L. Science 2000, 289, 1757; Pan, Y; Du, X.; Zhao, F.; Xu, B. Chem. Soc. Rev. 2012, 41, 2912). However, thus far, these types of “smart” ensembles have rarely been investigated in vivo owing primarily to these inherent physiological obstacles. One commonality among tumors is acidity; the microenvironment usually has a pH of ˜6.8 and endo/lysosomes experience even lower pH values of 5.0-5.5.
Magnetic resonance imaging (MRI) is the most effective imaging diagnosis equipment up to date that can form images of the organs of living humans or animals in a non-invasive way in real time. MRI contrasting agent helps each tissue and blood vessel to be shown more clearly, so that more precise diagnosis is possible.
There are two types of MRI contrasting agent: T1, which makes the target site brighter and T2, which makes it darker. Paramagnetic gadolinium complex is widely used as T1 contrasting agent, but low molecular weight of gadolinium complex makes the residence time within the blood vessel and body short, making exact diagnosis of vessel disease more difficult, and there has been a report that it may cause systemic fibrosis in a person with degraded kidney function.
Photodynamic therapy is a treatment that uses a photosensitizer which causes chemical reactions along with light and oxygen to selectively kill cells of a tissue in need of treatment. Unlike general anti-cancer drugs or radiation therapies which have an effect on normal tissue cells, photodynamic therapy has the advantage of greatly reducing the side effects of the anti-cancer drugs or radiation therapies, due to targeting and killing the cells of diseased tissues and selectively killing them.
The object of the present invention is to provide a pharmaceutical composition for photodynamic therapy, of which particle size is smaller than below 100 nm-sized holes on cancer tissue surface, wherein the surface charge of the composition changes from negative to positive when the composition reaches cancer tissues, thereby allowing for approach and penetration of the composition to the cancer tissues, and wherein the photosensitizer can selectively and effectively penetrate to the cancer tissues due to a linker which separates at an acidic condition of the cancer tissues, and thereby effectively killing cancer tissue cells by forming a large amount of reactive oxygen species activated by light and the photosensitizer.